DESCRIPTION: Despite the availability of a preventative vaccine, chronic hepatitis B virus (HBV) infection affects more than 240 million people worldwide and substantially increases the risk for developing serious liver diseases such as cirrhosis and hepatocellular carcinoma. Current therapies for chronic hepatitis B reduce viremia but rarely eliminate the infection, even after long-term administration of antiviral drugs. One promising new approach for treating chronic HBV infection is by therapeutic vaccination to induce an immune response that can control the virus. However, the vaccine platforms tested to date have lacked sufficient immunogenicity to overcome immune tolerance and eliminate HBV from the liver. Therefore, new safe vaccine systems that generate an effective therapeutic immune response to HBV are needed. Compared to other vaccine platforms, viral vectors have the advantage that they efficiently elicit broad CD8 T cell and antibody responses, but concerns about toxicity and systemic spread limit their widespread clinical use. In our previous published studies, we found that recombinant wild type vesicular stomatitis virus (VSV) expressing the HBV middle surface envelope glycoprotein (MHBs) induces effective immune responses in mouse models of acute and chronic HBV infection. We will now test the hypothesis that vaccine vectors based on two related and highly attenuated VSV-based vaccine platforms - VSVN4CT1 and virus-like vesicles (VLV) - will induce effective therapeutic immune responses to HBV. In preliminary studies, we generated VSVN4CT1 and VLV vectors that express MHBs, and found that these vectors induce HBV-specific immune responses in mice. Here, our general approach will be to characterize the immunogenicity and efficacy of VSVN4CT1 and VLV vectors expressing MHBs or HBV core antigen (HBcAg) using both normal mice and mouse models of acute and chronic HBV replication. To evaluate our hypothesis, we will carry out three aims. First, we will characterize the immunogenicity of VSVN4CT1 and VLV vectors expressing HBV antigens in normal mice. Second, we will evaluate vaccine efficacy in mouse models of acute and chronic HBV infection. Third, we will test prime-boost regimens to optimize HBV-specific immune responses. The proposed research is significant because an effective therapeutic vaccine that cures chronic HBV would have a substantial impact on the prevention of HBV-associated chronic liver diseases.